Amylin Pharmaceuticals Inc. and partner Eli Lilly and Co. released solid Phase III data on the last of the "three amigos" pivotal trials for exenatide, a first-in-class candidate being developed for Type II diabetes.
Each of the studies met its primary glucose-control endpoint as measured by hemoglobin A1C, which reflects average glucose levels over the prior three- to four-month period. The average reduction in A1C across the program in patients completing the studies on the highest dose of exenatide (10 micrograms twice daily) was about 1 percent.
In a conference call Tuesday, Ginger Graham, president and CEO of San Diego-based Amylin, said the partners expect to file a new drug application in mid-2004, but declined to comment on whether exenatide would be a candidate for priority review.
The "three amigos" program for the twice-daily injectable formulation of exenatide involved three successful Phase III trials of 336, 377 and 734 patients. Exenatide (synthetic exendin-4) is a 39-amino-acid peptide in-licensed by Amylin from an individual researcher, who was working on it at a very early development stage.
Graham said Amylin initiated human trials of exenatide in 1998, and by the time the new drug application is filed, upward of 2,000 people will have taken exenatide. "This is a monumental achievement," she said. "The level of scientific leadership, support from our investors and incredible work by the clinical research organizations has yielded results that we believe will form the basis of submission to the FDA and other regulatory agencies around the world."
Furthermore, Graham said Amylin and Lilly believe they can contribute to improving the lives of millions of patients living with diabetes. And in one significant way, trial data indicated that exenatide improves glucose control without weight gain.
"For those who understand the complexities and the challenge of diabetes, you will appreciate that improving glucose control without weight gain is a significant challenge for people with Type II diabetes," she said.
About 40 percent of patients (on the highest dose) achieved A1C measurements of 7 percent or less, and on average, those patients demonstrated reductions in body weight of about 2 kg. The most common adverse event was mild to moderate transient nausea, the company said.
Of the 734 randomized patients participating in the final Phase III, about two-thirds received exenatide and one-third received placebo.
To evaluate sulfonylurea-related hypoglycemia, patients in each treatment group were further randomized. Patients in the first group took their maximally effective dose of sulfonylurea unless hypoglycemia occurred, at which point they reduced their dose. Patients in the second group reduced their sulfonylurea dose before starting the study medication and were later instructed to titrate their dose to maximize glucose control.
Amylin said rates of mild to moderate hypoglycemia were higher in patients in the first group. Patients treated with the highest dose showed statistically significant reductions in A1C, compared to placebo, and a 35 percent incidence of mild to moderate hypoglycemia. The placebo arm demonstrated a mild to moderate hypoglycemia of 15 percent.
Meanwhile, patients in the second group ended the study with a significant reduction in A1C and a 21 percent incidence of mild to moderate hypoglycemia, compared to placebo.
As for the earlier trials, in August 2003 the partners reported that exenatide produced statistically significant, dose-dependent reductions in the primary glucose-control endpoint in a seven-month Phase III trial of people with Type II diabetes failing to achieve target blood-glucose levels. Patients receiving exenatide also showed statistically significant reductions in body weight, the company said. (See BioWorld Today, Aug. 8, 2003.)
Data from the second Phase III, released in early November, also demonstrated statistically significant, dose-dependent reductions in the glucose-control endpoint. That was a seven-month study in people with Type II diabetes failing to achieve target blood-glucose levels with sulfonylurea alone, the company said.
Amylin and Lilly, of Indianapolis, in September 2002 entered a deal potentially worth $435 million (for Amylin) to co-develop exenatide (then called AC2993). The agreement included a $110 million up-front payment to Amylin, Mark Foletta, Amylin's vice president of finance and chief finance officer, told BioWorld Today. Lilly paid about $30 million of that fee via a purchase of 1.6 million shares of Amylin's common stock.
The remainder of the financial deal includes $85 million in potential development milestones and about $130 million in commercialization milestones.
Foletta declined to specify the event that would trigger the next development milestone, but he did say the company likely would receive it by year's end.
As part of the deal with Lilly, Amylin is developing a long-acting-release formulation of exenatide, currently in Phase II trials.
Beyond exenatide, Amylin's Prescription Drug User Fee Act (PDUFA) date for Symlin (pramlintide acetate) is mid-December. Symlin is a proposed adjunctive therapy to insulin for the treatment of Type I or Type II diabetics who use insulin. (See BioWorld Today, Dec. 8, 2000; July 27, 2001; Oct. 15, 2001; and June 18, 2002.)
Amylin's stock (NASDAQ:AMLN) moved up $1.12 Tuesday to close at $26.22.